Lentiviruses are non-oncogenic retroviruses which cause chronic progressive neurological diseases with unusually long incubation periods. Visna virus in sheep, is the prototype of this group of viruses, which in addition to the progressive neurological disease causes chronic pneumonitis and arthritis. Lentiviruses cause persistent infections in vivo, replicating at a slow but continuous rate; in vitro they cause syncytia and cell lysis and replicate at a highly productive level. Regulation of gene expression of the lentiviruses, and visna virus in particular, involves both viral and cellular factors. The aim of this proposal is to investigate the mechanism of action of the viral and cellular factors involved in gene regulation of visna virus in vitro and in vivo. The results of the in vitro studies will determine the strategies used to study the events occurring in the animal during natural infection which influence viral latency and activation. A cDNA clone for the viral transacting genes has been isolated and experiments will be done to determine how these viral proteins regulate gene expression. Specifically, transcription rates and steady state levels of the viral mRNA will be measured and compared to protein levels to determine the level of action of viral regulatory genes. Studies will be done to determine if these proteins act by binding directly or indirectly to viral DNA or RNA. The cellular transcription factor AP-1 and the proto-oncogene c-fos have been implicated in the regulation of visna virus transcription; these and other cellular factors which bind to and activate gene expression from the visna virus LTR will be studied. Finally, the role of viral infection and viral regulatory proteins in the regulation of cellular genes will be investigated to determine how visna virus causes its pathogenetic effects in vivo without direct cell death.